For a patient with metastatic colon cancer who tested positive for MSI (i.e. MLH1 hypermethylation etc) and BRAF mutation, what would be your preferred choice in the second line setting?
What is your preferred second line treatment in MSI-H, BRAF V600E mutated metastatic colon CA?
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Approximately 15% of colorectal carcinomas demonstrate mismatch repair deficiency. The majority of these are MLH1/PMS2 deficient due to MLH1 promoter hypermethylation (MLH1ph). BRAF V600E mutations occur in approximately 50% of colorectal carcinomas with MLH1ph. The role of immunotherapy in patients with MMR-d malignancies is now well established with both pembrolizumab (Le et al NEJM 2015) and nivolumab/ipilimumab (Overman et al JCO 2018). Patients can have prolonged, deep responses, at the risk of having immune related toxicities.
The BEACON study (Kopetz et al NEJM 2020) demonstrated the efficacy for BRAF/MEK inhibition with anti-EGFR therapy for patients with BRAF V600E mutations. Interestingly, the doublet arm (cetuximab/encorafenib) did just as well as the triplet arm (cetuximab/encorafenib/binimetinib) with mOS of 9.3 months for both arms. Though this is very exciting, the duration of response is quite limited, with mPFS of ~4 months for both the doublet and triplet arms.
Additionally, both pembrolizumab and nivo/ipi have demonstrated higher response rates than the doublet BEACON study, which is an important consideration if a patient is very symptomatic from their disease burden.
Based on these data, I would opt to try immunotherapy first given the higher likelihood of prolonged and deeper responses, with plans to reserve the doublet BEACON regimen after progression.